Drug addiction is a complex and seemingly intractable disorder that exacts enormous financial and personal costs upon society. Behavioral responses to drugs of abuse require long-lasting adaptations in the function of dopamine (DA)-regulated reward networks in the brain. At the cellular level these adaptations are associated with mechanisms of synaptic plasticity that are mediated in part through the induction of new gene expression. Recently it has begun to be appreciated that epigenetic mechanisms of transcriptional regulation, which include alterations in DMA methylation and posttranslational modifications of histones, are key regulators of long-lasting changes in gene expression in the brain. The methyl-DNA binding transcriptional represser Methyl CpG Binding Protein 2 (MeCP2) is a strong candidate to mediate drug induced changes in gene expression, since one of its direct target is the brain derived-neurotrophic factor (BDNF) that is known to modulate the drug induced behavioral sensitization. We have found, in our preliminary results, that treatment of mice with the psychostimulants, cocaine or amphetamine rapidly induces phosphorylation of MeCP2 Ser421. This phosphorylation is selectively induced in neurons within the shell of the nucleus accumbens (NAc), a brain region that is known to play a central role in mediating the behavioral response to drugs of abuse. Injection of either a D1- or D2-like agonist is sufficient to drive MeCP2 Ser421 phosphorylation in NAc, consistent with a role for DA in the regulation of MeCP2 function by psychostimulants. On the basis of these data, we hypothesize that MeCP2 contributes to the regulation of pscyhostimulant-induced gene expression and the subsequent behavioral response to these drugs. To test this hypothesis we will further characterize the temporal and spatial induction of MeCP2 Ser421 phosphorylation in response to cocaine or amphetamine treatment in the mouse cortical-mesolimbic system. Secondly, we will knockout MeCP2 local in NAc or VTA, or mutate the MeCP2 Ser421 site globally to exam the potential effect to behavioral sensitization in responding to drugs of abuse. We anticipate that our proposed study will not only provide significantly new insights into the specific mechanisms of epigenetic regulation of drug-induced programs of gene expression, but may also offer new opportunities for understanding how these mechanisms contributes to the persistent modification of behavior in animal models of drug addiction and, eventually, lead to potential therapeutic solutions to abusive drug use.